Signals necessary for cell growth, differentiation, response to bioregulatory molecules, infectious agents and physiological stress involve changes in the rates of gene expression. The ability to respond appropriately to such signaling events challenges the survival of the cell and ultimately the organism. Pertrubations in the normal regulation of these specific genetic responses can result in pathogenic events that lead to acute and chronic diseases. In certain autoimmune diseases or chronic inflammatory states, continuous activation of T-cells eventually leads to a self-perpetuating destruction of normal tissues or organs. This caused by the induction of adhesion molecules, chemotaxis of leukocytes, activation of leukocytes and the production of mediators of inflammation, all of these events are regulated at the level of transcription for the production of new proteins, including cytokines. The production of cytokines, as well as a number of other cellular regulators, is controlled by a family of proteins, known as transcription factors (TFs). These transcription factors, when activated, bind to specific regions on the DNA and act as molecular switches or messengers to induce or upregulate gene expression. The activation of these TFs is caused by a variety of external signals including physiological stress, infectious agents and other bioregulatory molecules. Once the plasma membrane receptors are activated, a cascade of protein kinases and second messengers are induced which, in turn, result in the production of RNA transcripts. The end result is the production of RNA transcripts, and proinflammatory proteins via translation and processing of the RNA transcripts.
The activation system can, at times, be very robust. For example, a specific set of external signals could result in a single transcription factor to induce many proteins responsible for a given disease. Therefore, regulating this process by disrupting the production of activated TF(s) has the potential to attenuate the production of the associated pathological proteins, thereby halting or reversing the course of the disease.
Two transcription factors, NFkB and AP-1, have been show to regulate the production of many proinflammatory cytokines and related proteins that are elevated in immunoinflammatory diseases. These TFs regulate interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in a variety of cell types. For example, NFkB and other related complexes are involved in the rapid induction of genes whose products function in the protective and proliferative responses upon exposure of cells to external stimuli. Similarly, AP-1 has a significant role in the regulation of IL-2 and TNF-α transcription during T-cell activation. In addition, TNF-α and IL-1 are strong activators of collagenase, gelatinase and stromelysin gene expression, which require a single AP-1 binding site in the promoter region of these genes. Therefore, an inhibitor of NFkB and/or AP-1 activation would coordinately repress the activities of a series of proteinases. In addition, cell adhesion molecules are also controlled by these TFs. All of these proteins have shown to play a role in diseases, including osteoarthritis, transplant rejection, ischemia, reperfusion injury, trauma, certain cancers, viral disorders, and autoimmune diseases such a rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes, In summary, the role of these TFs is to act as a transducer for certain stimuli that lead to immune, inflammatory, and acute phase responses.
Since many diseases are caused by the inappropriate production of proteins, conventional therapeutic approaches have focused on inhibiting function or activity of individual effector proteins. These treatments have not always proved to be effective and, at times, are associated with many undesirable side effects. Therefore, there is a need for new therapies for the prevention and/or treatment of immunoinflammatory and autoimmune diseases. More specifically, there is a need for compounds that prevent, preferably by inhibiting transcription at an early stage, the production of proteins associated with immunoinflammatory and autoimmune diseases. Furthermore, these compounds should inhibit the kinase(s) that regulate the activation of TFs such as NFkB and AP-1. The present invention fulfills these needs and provides further related advantages.
The present invention is concerned with the treatment of immunological diseases or inflammation, notably such diseases are mediated by cytokines or cyclooxygenases. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and provide the necessary “help” for T cell stimulation and proliferation. Most importantly macrophages make IL-1, IL-12 and TNF-α all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFNγ). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by the immune cells and large numbers of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation rely at least in part on the activation of an enzyme on the cell signalling pathway, a member of the MAP known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
Cytokines are molecules secreted by the immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine, TNF-α, plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory diseases. TNF-α is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-α participates in the protective inflammatory response by activating leukocytes and promoting their migration to the extravascular sites of inflammation (Moser et al., J Clin Invest, 83, 444-55, 1989). At higher concentrations, TNF-α can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21, 2575-79, 1991; Brennan et al., Lancet, 2, 244-7, 1989). TNF-α also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-α mediates the cytokine cascade that leads to joint damage and destruction (Arend et al., Arthritis Rheum, 38, 151-60, 1995). Inhibitors of TNF-α, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21, 75-87, 1999) and anti-TNF-α antibody (infliximab) (Luong et al., Ann Pharmacother, 34, 743-60, 2000), have been recently approved by the U.S.FDA as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-α have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis etc.
Elevated levels of TNF-α and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-α.
It can be seen that inhibitors of TNF-α are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-α have been described in several patents. Excessive production of IL-6 is implicated in several disease states, and it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S. Pat. Nos. 6,004,813, 5,527,546 and 5,166,137.
The cytokine IL-1β also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandins from synovial cells. Elevated or unregulated levels of the cytokine IL-1β have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer's disease etc. Since overproduction of IL-1β is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1β.
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382, 1990). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than TNF-α. (Firestein, Am. J. Pathol. 140, 1309, 1992). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration have been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531, 1994).
In rheumatoid arthritis, both IL-1 and TNF-α induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis i.e.CIA in rats and mice) intra-articular administration of TNF-α either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253, 1992; and Cooper, Clin. Exp. Immunol. 898, 244, 1992).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into the sites of inflammation or injury (e.g., ischemia) is mediated; chemotactic nature of IL-8, including, but is not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminish, neutrophil infiltration.
It has been reported that Cyclooxygenase enzyme exists in three isoforms, namely, COX-1, COX-2 and COX-3. COX-1 enzyme is essential and primarily responsible for the regulation of gastric fluids, whereas COX-2 enzyme is present at the basal levels and is reported to have a major role in the prostaglandin synthesis for inflammatory response. These prostaglandins are known to cause inflammation in the body. Hence, if the synthesis of these prostaglandins is stopped by way of inhibiting COX-2 enzyme, inflammation and its related disorders can be treated. COX-3 possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and COX-2 demonstrated, that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, dipyrone, and is potently inhibited by some nonsteroidal anti-inflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. Earlier reports prior to Coxib's development show that inhibitors of COX-1 enzyme cause gastric ulcers, whereas selective COX-2 and COX-3 enzyme inhibitors are devoid of this function and hence are found to be safe. But, recent reports show that the selective COX-2 inhibitors (Coxib's) are associated with cardiovascular risks. So, inhibition of COX-2 without causing cardiovascular risks and gastric ulcers due to inhibition of COX-1 is shown to be safe and is concerned in the present invention.
Cardiovascular pathologies that remain the leading cause of mortality and morbidity in western society include several diseases, such as ishemic cardiopathy of which myocardial infarction represents the most important form. Ischemic cardiopathy is characterized by an inadequacy between supply and demand in oxygenated blood correlated with a diminution of coronary blood flow due to coronary artery stenosis or occlusion. This artery occlusion often caused by atherosclerous lesions, acute thrombosis, edema, ballooning of atheromatous plaque, or bleeding (Pearson et al., Am. J. Pathol, 86, 657-664, 1977; Horie et al, Br Heart J. 40: 153-161, 1978; Koenig, Cardiol. Review, 9:31-35, 2001). TXA2 is a potent platelet activator and constrictor of vascular and bronchial smooth muscles. TXA2 is a short live lipidic mediator generated by the cyclooxygenase pathway, is mainly produced by platelets, macrophages, and lung parenchyma. TXA2 is a potent platelet activator and constrictor of vascular and bronchial smooth muscles. It has been demonstrated that drugs able to antagonize TXA2 receptors or to inhibit thromboxane synthase (TS) reduce the severity of myocardial ischemia (Schror et al, Am. J. Physiol, 238: 87-92, 1980; Burke et al, Br J Clin Pharmacol, 15:97S-101S, 1983; Hock et al, Eur. J. Pharmacol, 122:213-219, 1986; Brezinsky et al, J. Cardio-vasc Pharmacol, 9:65-71, 1987) and is also concerned in the present invention.
Few Prior Art References, which Disclose the Closest Compounds, are Given Below:
    i) WO 2005/084368 discloses novel compounds of formula,
wherein, each  independently represents a single or double bond; either (a) A, B and E are independently CR1, C(R1)2, NR1 or N; or (b) B is joined with A or E to form a fused 5- to 8-membered partially satured ring that is substituted with 0 to 3 substituents, independently selected from R1, and the other of A or E is CR1, C(R1)2, NR1, or N; D and G are independently CR1, C(R1)2, NR1; W, X, Y and Z are independently CR1 and N; P, Q, T and V are independently CR1, C(R1)2, N or NF; or Q is taken together with V or P to form a fused 5-to 7-membered carbocycle or heterocycle that is substituted with from 0 to 4 substitutents, independently chosen from Rb; R1 is independently chosen at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro and groups of the formula L-M; L is independently chosen at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O)m, N(Rx), C(═O)N(Rx), N(Rx)C(═O), N(Rx) S(O)m, S(O)m N(Rx) and N[S(O)mRx]S(O)m; wherein m is independently selected at each occurrence from 0, 1 and 2 and M is independently selected at each occurrence from (a) hydrogen; and (b) C1-C8 alkyl, C2-C8alkenyl, C2-C8alkynyl, mono- and di-(C1-C4alkyl)aminoC0-C4alkyl, phenylC0-C4alkyl, C3-C8cycloalkylC0-C4alkyl, (5-membered heteroaryl)C0-C4alkyl, and (5- to 7-membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0-5 substitutents independently selected from Rb; J1 chosen form O, NH and S; U is C1-C3alkyl, substituted with from 0 to 3 substitutents independently chosen from oxo and C1-C3alkyl, or two substitents are taken together to form a 3- to 7-membered cycloalkyl or heterocycloalyl. The invention further relates to the use of such compounds for treating conditions related to capsaicin receptor activation, for identifying other agents that bind to capsaicin receptor, and as probes for the detection and localization of capsaicin receptor. An example of these compounds is shown below in formula (1)
    ii) U.S. Pat. No. 5,811,428 discloses the following general structure,
    wherein A is C—R6 when B is N, and A is N when B is C—R1, and wherein R1, R2, R4, R5 and R6 are as defined below. Thus, when A is C—R6 and B is N, structure (I) is a pyrimidine-containing compound having structure (II), and when A is N and B is C—R1, structure (I) is a pyrazine containing compound having structure (III). The inventions relates generally to compounds that block intracellular signal transduction and activation of transcription factors, and to methods for preventing or treating immunoinflammatory and autoimmune diseases.
Examples of these compounds are shown below,
    iii) U.S. Pat. No. 6,835,726 discloses the following general structure,    in which X represents —NR3R4, —OR3, —SR3, aryl, alkyl or arylakyl. The letter Y represents a covalent bond, —N(R6)—, —O—, —S—, —C(═O)— or an alkylene group. R1 and R2 are independently selected from hydrogen, alkyl, —O-alkyl, —S-alkyl, aryl, arylalkyl, —O-aryl, —S-aryl, —NO2, —NR7R8, —C(O)R9, —CO2R10, —C(O)NR7R8, —N(R7)C(O)R9, —N(R7)CO2R11, —N(R9)C(O)NR7R8, —S(O)mNR7R8, —S(O)nR9, —CN, halogen, and —N(R7)S(O)mR11. R5 and R6 are independently hydrogen, alkyl, aryl or aralkyl. Compounds and compositions are provided which are useful for the treatment of viral infections particularly human cytomegalovirus infection.Examples of these compounds are shown below,
    iv) US 2005/0065145 A1 discloses DPP-IV inhibitors of the following general structure:
    wherein, Q is selected from the group consisting of CO, SO, SO2, and C═NR4; Z is a leaving group, selected from the group consisting of halo, perhalo (C1-10) alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6, or 7 membered ring; R2 is selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-12)cycloalkyl, (C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkyl(C1-5)alkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, (C9-12)bicycloaryl(C1-5)alkyl, hetero(C4-12)bicycloaryl, hetero(C8-12)bicycloaryl(C1-5)alkyl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R2 is not NH or N═CH; R3 is selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, amino, cyano, nitro, thio, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or where R2 and R3 are taken together to form a ring; R4 is selected from the group consisting of hydrogen, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, bicycloaryl, heterobicycloaryl, each substituted or unsubstituted; L is a linker providing 0-6 atom separation between X and the ring to which L is attached; X is selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
